Genetics and cell biology

Gene expression and muscular dystrophy

team-item

Head of unit

Davide Gabellini

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Only about 1% of our genome encodes for the ~20000 human proteins, which are similar in number and largely orthologous to those found in organisms of significant lower complexity. Interestingly, up to two thirds of our genome is composed of repetitive sequences that are dynamically transcribed in different cells and developmental stages producing a vast pool of ncRNAs. Thus, ncRNAs produced by DNA repeats may hold the key to understanding the regulatory complexity inherent in advanced biological networks. Nevertheless, their biological relevance and mechanism of action remain poorly explored.

Research activity

The unit main interest is to understand how gene expression instructs the complex programs typical of higher eukaryotes. We are particularly interested in the regulation of muscle- and B-cell differentiation, and the associated diseases using FSHD muscular dystrophy and acute lymphoblastic leukemia, respectively, as paradigms. FSHD is the most prevalent neuromuscular disease affecting males and females of all ages. The disease is caused by chromatin relaxation leading to inappropriate gain of expression of the double homeobox transcription factor DUX4, which is highly toxic to skeletal muscle leading to disease. B cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer and the major cause of cancer-related death among children and young adults. DUX4 translocations have been reported in up to 7% of B-ALL patients and define a new B-ALL subtype, characterized by deregulation of the ETS transcription factor gene ERG, and widespread hypomethylation compared to normal B cells or other ALL subtypes. DUX4 rearrangements in B-ALL mostly involve insertion of a C-terminally truncated DUX4 sequence retaining the DNA binding domain of WT DUX4 in the immunoglobulin heavy chain (IGH) locus leading the production of the oncogenic DUX4-IGH fusion protein under the control of the IGH enhancer. We combine biochemistry, cell biology and molecular biology tools together with genome wide approaches in order to understand the mechanisms controlling DUX4 and DUX4-IGH expression and activity. We evaluate the therapeutic relevance of our findings using cellular and animal models of the diseases.